ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo

David R. Gibb, Mohey El Shikh, Dae Joong Kang, Warren J. Rowe, Rania El Sayed, Joanna Cichy, Hideo Yagita, John G. Tew, Peter J. Dempsey, Howard C. Crawford, Daniel H. Conrad

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

The proteolytic activity of a disintegrin and metalloproteinase 10 (ADAM10) regulates cell-fate decisions in Drosophila and mouse embryos. However, in utero lethality of ADAM10-/-mice has prevented examination of ADAM10 cleavage events in lymphocytes. To investigate their role in B cell development, we generated B cell-specific ADAM10 knockout mice. Intriguingly, deletion of ADAM10 prevented development of the entire marginal zone B cell (MZB) lineage. Additionally, cleavage of the low affinity IgE receptor, CD23, was profoundly impaired, but subsequent experiments demonstrated that ADAM10 regulates CD23 cleavage and MZB development by independent mechanisms. Development of MZBs is dependent on Notch2 signaling, which requires proteolysis of the Notch2 receptor by a previously unidentified proteinase. Further experiments revealed that Notch2 signaling is severely impaired in ADAM10-null B cells. Thus, ADAM10 critically regulates MZB development by initiating Notch2 signaling. This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer.

Original languageEnglish (US)
Pages (from-to)623-635
Number of pages13
JournalJournal of Experimental Medicine
Volume207
Issue number3
DOIs
StatePublished - Mar 15 2010
Externally publishedYes

Fingerprint

Disintegrins
Metalloproteases
B-Lymphocytes
Notch2 Receptor
IgE Receptors
Null Lymphocytes
Cell Lineage
Knockout Mice
Proteolysis
Drosophila
Hypersensitivity
Peptide Hydrolases
Embryonic Structures
Lymphocytes
Pathology

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Gibb, D. R., El Shikh, M., Kang, D. J., Rowe, W. J., El Sayed, R., Cichy, J., ... Conrad, D. H. (2010). ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. Journal of Experimental Medicine, 207(3), 623-635. https://doi.org/10.1084/jem.20091990

ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. / Gibb, David R.; El Shikh, Mohey; Kang, Dae Joong; Rowe, Warren J.; El Sayed, Rania; Cichy, Joanna; Yagita, Hideo; Tew, John G.; Dempsey, Peter J.; Crawford, Howard C.; Conrad, Daniel H.

In: Journal of Experimental Medicine, Vol. 207, No. 3, 15.03.2010, p. 623-635.

Research output: Contribution to journalArticle

Gibb, DR, El Shikh, M, Kang, DJ, Rowe, WJ, El Sayed, R, Cichy, J, Yagita, H, Tew, JG, Dempsey, PJ, Crawford, HC & Conrad, DH 2010, 'ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo', Journal of Experimental Medicine, vol. 207, no. 3, pp. 623-635. https://doi.org/10.1084/jem.20091990
Gibb, David R. ; El Shikh, Mohey ; Kang, Dae Joong ; Rowe, Warren J. ; El Sayed, Rania ; Cichy, Joanna ; Yagita, Hideo ; Tew, John G. ; Dempsey, Peter J. ; Crawford, Howard C. ; Conrad, Daniel H. / ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. In: Journal of Experimental Medicine. 2010 ; Vol. 207, No. 3. pp. 623-635.
@article{0aadaf32236f4eec8298a96c79276899,
title = "ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo",
abstract = "The proteolytic activity of a disintegrin and metalloproteinase 10 (ADAM10) regulates cell-fate decisions in Drosophila and mouse embryos. However, in utero lethality of ADAM10-/-mice has prevented examination of ADAM10 cleavage events in lymphocytes. To investigate their role in B cell development, we generated B cell-specific ADAM10 knockout mice. Intriguingly, deletion of ADAM10 prevented development of the entire marginal zone B cell (MZB) lineage. Additionally, cleavage of the low affinity IgE receptor, CD23, was profoundly impaired, but subsequent experiments demonstrated that ADAM10 regulates CD23 cleavage and MZB development by independent mechanisms. Development of MZBs is dependent on Notch2 signaling, which requires proteolysis of the Notch2 receptor by a previously unidentified proteinase. Further experiments revealed that Notch2 signaling is severely impaired in ADAM10-null B cells. Thus, ADAM10 critically regulates MZB development by initiating Notch2 signaling. This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer.",
author = "Gibb, {David R.} and {El Shikh}, Mohey and Kang, {Dae Joong} and Rowe, {Warren J.} and {El Sayed}, Rania and Joanna Cichy and Hideo Yagita and Tew, {John G.} and Dempsey, {Peter J.} and Crawford, {Howard C.} and Conrad, {Daniel H.}",
year = "2010",
month = "3",
day = "15",
doi = "10.1084/jem.20091990",
language = "English (US)",
volume = "207",
pages = "623--635",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "3",

}

TY - JOUR

T1 - ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo

AU - Gibb, David R.

AU - El Shikh, Mohey

AU - Kang, Dae Joong

AU - Rowe, Warren J.

AU - El Sayed, Rania

AU - Cichy, Joanna

AU - Yagita, Hideo

AU - Tew, John G.

AU - Dempsey, Peter J.

AU - Crawford, Howard C.

AU - Conrad, Daniel H.

PY - 2010/3/15

Y1 - 2010/3/15

N2 - The proteolytic activity of a disintegrin and metalloproteinase 10 (ADAM10) regulates cell-fate decisions in Drosophila and mouse embryos. However, in utero lethality of ADAM10-/-mice has prevented examination of ADAM10 cleavage events in lymphocytes. To investigate their role in B cell development, we generated B cell-specific ADAM10 knockout mice. Intriguingly, deletion of ADAM10 prevented development of the entire marginal zone B cell (MZB) lineage. Additionally, cleavage of the low affinity IgE receptor, CD23, was profoundly impaired, but subsequent experiments demonstrated that ADAM10 regulates CD23 cleavage and MZB development by independent mechanisms. Development of MZBs is dependent on Notch2 signaling, which requires proteolysis of the Notch2 receptor by a previously unidentified proteinase. Further experiments revealed that Notch2 signaling is severely impaired in ADAM10-null B cells. Thus, ADAM10 critically regulates MZB development by initiating Notch2 signaling. This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer.

AB - The proteolytic activity of a disintegrin and metalloproteinase 10 (ADAM10) regulates cell-fate decisions in Drosophila and mouse embryos. However, in utero lethality of ADAM10-/-mice has prevented examination of ADAM10 cleavage events in lymphocytes. To investigate their role in B cell development, we generated B cell-specific ADAM10 knockout mice. Intriguingly, deletion of ADAM10 prevented development of the entire marginal zone B cell (MZB) lineage. Additionally, cleavage of the low affinity IgE receptor, CD23, was profoundly impaired, but subsequent experiments demonstrated that ADAM10 regulates CD23 cleavage and MZB development by independent mechanisms. Development of MZBs is dependent on Notch2 signaling, which requires proteolysis of the Notch2 receptor by a previously unidentified proteinase. Further experiments revealed that Notch2 signaling is severely impaired in ADAM10-null B cells. Thus, ADAM10 critically regulates MZB development by initiating Notch2 signaling. This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer.

UR - http://www.scopus.com/inward/record.url?scp=77949528417&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77949528417&partnerID=8YFLogxK

U2 - 10.1084/jem.20091990

DO - 10.1084/jem.20091990

M3 - Article

VL - 207

SP - 623

EP - 635

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 3

ER -